Nitric Oxide (NO) donors are known to be useful for therapeutic utility, e.g., to prevent restenosis following angioplasty (Gloves, P., et al., Cardiovascular Research 26, 615-619 (1992)), to inhibit platelets to prevent coagulation and thrombus formation (Groves, P., et al., Circulation 87, 590-597 (1993)) and to treat angina (Knight, et al., Circulation 95, 125-132 (1997)). NO donors are considered to have additional therapeutic utility in cancer, killing microbes and viruses, relaxing airways and intestinal smooth muscle (e.g., for treating asthma and esophageal spasms), in promoting erectile function and in treatment of heart failure and urinary incontinence.
Nitric oxide can exist in three forms, namely in the oxidized form as nitrosonium ion (NO+), as neutral nitric oxide (the stable free radical NO.) and in the reduced form as nitroxyl ion (NO−).
The three forms are considered to have different physiological functions.
Administration of nitrosonium ion is favored for signaling receptors. The C-nitroso compounds that are the subject of the following set of patents where one of the inventors herein is a co-inventor, donate nitric oxide in the form of nitrosonium ion: see U.S. Pat. Nos. 6,359,182; 6,538,116; 6,887,994; 7,030,238 and 7,049,308. These C-nitroso compounds generate nitrosonium instead of nitroxyl because the nitroso is derived from a carbon acid with relatively low pKa so that there is no beta proton acidic enough to cause beta elimination between the nitroso and the beta proton.
Administration of neutral nitric oxide is favored for vasodilation and to inhibit aggregation of platelets and functions by nitrosylating the iron moiety of heme or nitrosylating G-protein.
Administration of nitroxyl ions increases cardiac output and reduces venous output for treatment of heart failure and protects against reperfusion injury.
While donors of neutral nitric oxide are known, e.g., sodium nitroprusside, the known neutral nitric oxide donors are unstable and therefore have storage stability problems and/or are spontaneously converted to neutral nitric oxide, and because of the low stability, are only useful for treating acute conditions, e.g., hypertensive emergency and to decrease myocardial oxygen demand after acute myocardial infarction and to increase cardiac output in congestive heart failure or when short-term reduction of cardiac preload and/or afterload is desired.
It has been discovered herein that problems currently limiting the therapeutic use of neutral nitric oxide donors can be overcome by preparing compound that releases neutral nitric oxide in a second order reaction. As used herein, the term “second order reaction” means reaction where the reaction rate depends on the concentration of one reactant raised to the second power or the concentration of two different reactants each raised to the first power.